n-Butyllithium/N,N,N',N'-tetramethylethylenediamine-mediated ortholithiations of aryl oxazolines: Substrate-dependent mechanisms

Article abstract of DOI:10.1021/ja068057u

n-Butyllithium/N,N,N′,N′-tetramethylethylenediamine-mediated ortholithiations of aryloxazolines are described. Methyl substituents on the aryloxazoline and substituents at the meta position of the arenes (methoxy, oxazolinyl, and fluoro) influence the rates and the mechanisms. Monomer- and dimer-based reactions are implicated. Density functional calculations probe details of the mechanism and suggest the origins of cooperative effects in meta-substituted aryl oxazolines.

Full text of DOI:10.1021/ja068057u

Published on Web 02/02/2007
n-Butyllithium/N,N,N′,N′-Tetramethylethylenediamine-Mediated
Ortholithiations of Aryl Oxazolines: Substrate-Dependent
Mechanisms
Scott T. Chadwick, Antonio Ramirez, Lekha Gupta, and David B. Collum*
Contribution from the Department of Chemistry and Chemical Biology, Baker Laboratory,
Cornell UniVersity, Ithaca, New York 14853-1301
Received November 15, 2006; E-mail: dbc6@cornell.edu
Abstract: n-Butyllithium/N,N,N′,N′-tetramethylethylenediamine-mediated ortholithiations of aryloxazolines
are described. Methyl substituents on the aryloxazoline and substituents at the meta position of the arenes
(methoxy, oxazolinyl, and fluoro) influence the rates and the mechanisms. Monomer- and dimer-based
reactions are implicated. Density functional calculations probe details of the mechanism and suggest the
origins of cooperative effects in meta-substituted aryl oxazolines.
Introduction
anisole, and several alkoxy-substituted aromatics by n-BuLi/
TMEDA mixtures (N,N,N′,N′-tetramethylethylenediamine) are
Ortholithiations were first described by Wittig and Gilman
in the 1930s.1 Using a protocol that was remarkably selective
for the era, they treated anisole with n-butyllithium (n-BuLi)
to generate an aryllithium that could be functionalized with
electrophiles (eq 1). They suggested that the selective and facile
metalation was caused by the increased acidity of the ortho
protons. Of course, as the applications of ortholithiations
expanded, an understanding of the underlying organolithium
chemistry also evolved.2 Solvent-dependent regioselectivities3,4
suggested mechanistic complexity. Despite a paucity of detailed
mechanistic studies of ortholithiations,5 the seemingly simple
notions of Wittig and Gilman have given way to more ornate
models. It is now widely accepted that ortholithiations involve
coordination of the ortho substituents to the lithium cation during
the rate-limiting proton transfer.6
congruent with Schlosser’s results.8 Relative rate constants
(krel) span a range of 60 000, eliciting a considerable number
of mechanistic hypotheses.1-11 Nonetheless, benzene and several
alkoxy-substituted aromatics metalate via transition structures
[(n-BuLi)2(TMEDA)2(ArH)]q, which were suggested to be based
on triple ions exemplified by 1.8,12 Electronic effects appear to
dominate, whereas the importance of coordination by alkoxy
groups is less clear. Mechanistic studies of n-BuLi/TMEDA-
mediated ortholithiations have been thoroughly summarized by
Saa´.11b
We report herein rate studies of the n-BuLi/TMEDA-mediated
ortholithiations of arenes 2-8 (Chart 1, eq 2). Ortholithiations
of aryl oxazolines, first investigated by Gschwend and Hamdan4
and Meyers and Mihelich,13 are very rapid compared with those
of anisoles bearing weakly directing methoxy moieties.2,14-16
The regioselectivity of a constrained oxazoline reported by
Although many ortholithiations may be directed by metal-
substituent interactions at the rate-limiting transition structure,
summary dismissal of Wittig’s and Gilman’s original hypothesis
may have been hasty. Extensive studies by Schlosser and co-
workers reveal that ortholithiation rates do indeed correlate with
acidities in some substrate classes.7 Lithiations of benzene,
(6) (a) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem.,
Int. Ed. 2004, 43, 2206. (b) Hartung, C. G.; Snieckus, V. In Modern
Arene Chemistry; Astruc, D., Ed.; Wiley-VCH: Weinheim, Germany,
2002; pp 330-367. (c) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19,
356.
(7) (a) Schlosser, M. Angew. Chem., Int. Ed. 2005, 44, 376. (b) Maggi, R.;
Schlosser, M. Tetrahedron Lett. 1999, 40, 8797. (c) Schlosser, M.; Mongin,
F.; Porwisiak, J.; Dmowski, W.; Bu¨ker, H. H.; Nibbering, N. M. M. Chem.
Eur. J. 1998, 4, 1281. (d) Schlosser, M. Angew. Chem., Int. Ed. Engl. 1998,
37, 1497.
(1) (a) Wittig, G.; Pockels, U.; Droge, H. Chem. Ber. 1938, 71, 1903. (b)
Gilman, H.; Bebb, R. L. J. Am. Chem. Soc. 1939, 61, 109.
(2) (a) Gschwend, H. W.; Rodriguez, H. R. Org. React. (N.Y.) 1979, 26, 1. (b)
Snieckus, V. Chem. ReV. 1990, 90, 879. (c) Ager, D. J.; Prakash, I.; Schaad,
D. R. Chem. ReV. 1996, 96, 835. (d) Clayden, J. Organolithiums: SelectiVity
for Synthesis; Tetrahedron Organic Chemistry, Vol. 23; Pergamon: Oxford,
2002.
(3) Shimano, M.; Meyers, A. I. J. Am. Chem. Soc. 1994, 116, 10815.
(4) Gschwend, H. W.; Hamdan, A. J. Org. Chem. 1975, 40, 2008.
(5) Hay, D. R.; Song, Z.; Smith, S. G.; Beak, P. J. Am. Chem. Soc. 1988, 110,
8145.
(8) (a) Chadwick, S. T.; Rennels, R. A.; Rutherford, J. L.; Collum, D. B.
J. Am. Chem. Soc. 2000, 122, 8640. (b) Rennels, R. A.; Maliakal, A. J.;
Collum, D. B. J. Am. Chem. Soc. 1998, 120, 421.
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J. AM. CHEM. SOC. 2007, 129, 2259-2268
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A R T I C L E S
Chart 1a
Chadwick et al.
Table 1. Summary of Rate Studies for the n-BuLi/
TMEDA-Mediated Ortholithiation of Arenes 3-5 and 8a
ArH
temp
n-BuLi order
kH/kD
3
4
5
8
-78 °C
-40 °C
-78 °C
-40 °C
0.94 ( 0.03
0.69 ( 0.04
1.00 ( 0.04
0.60 ( 0.02
27 ( 4
20 ( 3
32 ( 5
22 ( 3
a Chart 1.
the cosolvent.21 n-BuLi concentrations (0.050-1.0 M) were
maintained high relative to arenes (e0.02) to ensure pseudo-
first-order conditions.22 (Precipitations of the aryllithiums occur
at substrate concentrations greater than 0.05 M). n-BuLi/
TMEDA forms disolvated dimer 9 at all n-BuLi and TMEDA
concentrations studied.23 In situ IR spectroscopy reveals absor-
bances of arenes 2-8 at 1655 cm-1 and their corresponding
lithiated forms at 1635 cm-1. Arene-BuLi complexes, evi-
denced by a 10 to 30 cm-1 shift of the CdN stretch to lower
frequencies,24 were not observable in the presence of TMEDA.
a Relative rate constants adjusted to -40 °C are shown in parentheses.
Sammakia and Latham implicates an N-directed rather than an
O-directed metalation (eq 3).17
In all cases, loss of starting material follows clean first-order
decay to five half-lives. The rate constants are invariant ((10%)
over 10-fold arene concentrations, confirming the first-order
dependence on arene. Substantial kinetic isotope effects (Table
1), determined by comparing metalations of 3-5 and 8 with
We find that the substrate-dependent ortholithiation rates
(listed in parentheses in Chart 1) derive from monomer- and
dimer-based mechanisms. Density functional theory (DFT)
computations underscore the importance of N-Li and O-Li
interactions and offer insights into the substrate dependencies.
Of potential greatest interest to synthetic chemists, we examine
how meta-disposed directing substituents function cooperatiVely.
Nonspecialists will find a summary of the results at the start of
the discussion section.
(11) (a) Saa´, J. M.; Deya, P. M.; Sun˜er, G. A.; Frontera, A. J. Am. Chem. Soc.
1992, 114, 9093. (b) Saa´, J. M. HelV. Chim. Acta 2002, 85, 814.
(12) For an attempted compilation of a comprehensive bibliography of triple
ions of lithium salts, see: Ma, Y.; Ramirez, A.; Singh, K. J.; Keresztes, I.;
Collum, D. B. J. Am. Chem. Soc. 2006, 128, 15399.
(13) Meyers, A. I.; Mihelich, E. D. J. Org. Chem. 1975, 40, 3158.
(14) (a) Beak, P.; Brown, R. A. J. Org. Chem. 1979, 44, 4463. (b) Meyers,
A. I.; Lutomski, K. J. Org. Chem. 1979, 44, 4464.
(15) For a quantitative determination of pKa values of monosubstituted benzenes
in THF, see: Fraser, R. R.; Bresse, M.; Mansour, T. S. J. Am. Chem. Soc.
1983, 105, 7790.
(16) (a) Catalan, J.; Yan˜ez, M. J. Am. Chem. Soc. 1979, 101, 3490. (b) Lau,
Y. K.; Kebarle, P. J. Am. Chem. Soc. 1976, 98, 7452.
(17) (a) Sammakia, T.; Latham, H. A. J. Org. Chem. 1996, 61, 1629. For related
studies showing lithiated oxazolines that display N-Li rather than O-Li
contacts, see: (b) Stol, M.; Snelders, D. J. M.; de Pater, J. J. M.; van Klink,
G. P. M.; Kooijman, H.; Spek, A. L.; van Koten, F. Organometallics 2005,
24, 743. (c) Jayasuriya, K.; Alster, J.; Politzer, P. J. Org. Chem. 1988, 53,
677. (d) Jantzi, K. L.; Guzei, I. A.; Reich, H. J. Organometallics 2006, 25,
5390.
Results
A. Rate Studies.18 n-BuLi was twice recrystallized from
concentrated pentane solutions at -90 °C.19 TMEDA was
purified via recrystallization of the HCl salt.8a,20 TMEDA
concentrations (0.50-5.0 M) were adjusted using pentane as
(9) For a report describing a 200:1 preference for the n-BuLi/TMEDA-mediated
lithiation of anisole relative to benzene, see: Broaddus, C. D. J. Org. Chem.
1970, 35, 10.
(18) (a) For a tutorial on solution kinetics of organolithium reactions, see:
Collum, D. B.; McNeil, A. J.; Ramirez, A. Angew. Chem., Int. Ed. 2007,
45, in press. (b) For earlier summaries of organolithium mechanism, see:
Wardell, J. L. In ComprehensiVe Organometallic Chemistry; Wilkinson,
G.; Stone, F. G. A.; Abel, E. W., Eds.; Pergamon: New York, 1982; Vol.
1, Chapter 2. Ions and Ion Pairs in Organic Reactions; Szwarc, M., Ed.;
Wiley: New York, 1972; Vols. I,II.
(10) (a) Nguyen, T.-H.; Castanet, A.-S.; Mortier, J. Org. Lett. 2006, 8, 765. (b)
Anderson, D. R.; Faibish, N. C.; Beak, P. J. Am. Chem. Soc. 1999, 121,
7553. (c) Slocum, D. W.; Dietzel, P. Tetrahedron Lett. 1999, 40, 1823. (d)
Saa`, J. M.; Martorell, G.; Frontera, A. J. Org. Chem. 1996, 61, 5194. (e)
Slocum, D. W.; Thompson, J.; Friesen, C. Tetrahedron Lett. 1995, 36, 8171.
(f) Slocum, D. W.; Moon, R.; Thompson, J.; Coffey, D. S.; Li, J. D.;
Slocum, M. G.; Siegel, A.; Gayton-Garcia, R. Tetrahedron Lett. 1994, 35,
385. (g) van Eikema Hommes, N. J. R.; Schleyer, P. v. R. Tetrahedron
1994, 50, 5903. (h) van Eikema Hommes, N. J. R.; Schleyer, P. v. R. Angew.
Chem., Int. Ed. Engl. 1992, 31, 755. (i) Saa`, J. M.; Deya`, P. M.; Sun˜er,
G. A.; Frontera, A. J. Am. Chem. Soc. 1992, 114, 9093. (j) Bauer, W.;
Schleyer, P. v. R. J. Am. Chem. Soc. 1989, 111, 7191. (k) Kminek, I.;
Kaspar, M.; Trekoval, J. Collect. Czech. Chem. Commun. 1981, 46, 1124.
(l) Rausch, M. D.; Ciapenelli, D. J. J. Organomet. Chem. 1967, 10, 127.
(m) Screttas, C. G.; Eastham, J. F. J. Am. Chem. Soc. 1965, 87, 3276. (n)
Eberhardt, G. G.; Butte, W. A. J. Org. Chem. 1964, 29, 2928. (o) Stratakis,
M. J. Org. Chem. 1997, 62, 3024. (p) Fagley, T. F.; Klein, E. J. Am. Chem.
Soc. 1955, 77, 786.
(19) (a) Hoffmann, D.; Collum, D. B. J. Am. Chem. Soc. 1998, 120, 5810. (b)
Kottke, T.; Stalke, D. Angew. Chem., Int. Ed. Engl. 1993, 32, 580.
(20) Freund, M.; Michaels, H. Ber. Dtsch. Chem. Ges. 1897, 30, 1374.
(21) [n-BuLi] refers to the concentration of the monomer subunit (normality).
[TMEDA] refers to the molarity of the excess (uncoordinated) TMEDA.
(22) The low arene concentrations preclude the formation of substantial
concentrations of ArLi mixed aggregates. For studies of n-BuLi/ArLi
heteroaggregates formed during ortholithiations, see: Kronenburg,
C. M. P.; Rijnberg, E.; Jastrzebski, J. T. B. H.; Kooijman, H.; Lutz, M.;
Spek, A. L.; Gossage, R. A.; van Koten, G. Chem.sEur. J. 2005, 11, 253.
Gossage, R. A.; Jastrzebski, J. T. B. H.; van Koten, G. Angew. Chem., Int.
Ed. 2006, 44, 1448.
(23) Hoffmann, D.; Collum, D. B. J. Am. Chem. Soc. 1998, 120, 5810 and
references cited therein.
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Ortholithiations of Aryl Oxazolines
A R T I C L E S
Figure 3. Plot of kobsd vs [n-BuLi] in TMEDA (0.50 M) and pentane
cosolvent for the ortholithiation of 2-phenyl-5,6-dihydro-4H-1,3-oxazine
(8, 0.02 M) at -40 °C. The curve depicts the result of an unweighted least-
squares fit to kobsd ) k[n-BuLi]n affording k ) (3.8 ( 0.1) × 10-3, n )
0.60 ( 0.02. Alternatively, a fit to kobsd ) k[n-BuLi]1/2 + k′[n-BuLi] affords
Figure 1. Plot of kobsd vs [TMEDA] in pentane cosolvent for the
ortholithiation of 4-methyl-2-phenyl-4,5-dihydrooxazole (3, 0.02 M) by
n-BuLi (0.50 M) at -78 °C. The curve depicts the result of an unweighted
least-squares fit to kobsd ) k[TMEDA] + k′ (k ) (2 ( 1) × 10-5, k′ )
(9.5 ( 0.3) × 10-4).
k ) (2.7 ( 0.2) × 10-3, k′ ) (1.1 ( 0.2) × 10-3
.
parentheses in Chart 1. The relative rate constants are normalized
to oxazoline 4. The analogous temperature-corrected values of
krel for the ortholithiation of benzene, anisole, and resorcinol
dimethyl ether of 10-5, 10-2, and 1.0, respectively, serve as
benchmarks.8a
Rate Laws. The ortholithiations of arenes 3-5 and 8 were
investigated in detail and shown to be independent of TMEDA
concentrations (Figure 1), consistent with a mechanism requiring
no net change in the per-lithium solvation number on progres-
sion from 9 to the rate-limiting transition structures. Limited
positive or negative deviations fall well within the generalized
medium effects noted previously.8,27
The influence of n-BuLi concentration on rates shows
significant substrate dependence. The ortholithiations of arenes
3 and 5 are linearly dependent on n-BuLi concentration (Table
1; Figure 2). The idealized28 rate law (eq 4) implicates the
general lithiation mechanism described by eq 5.
Figure 2. Plot of kobsd vs [n-BuLi] in TMEDA (0.50 M) and pentane
cosolvent for the ortholithiation of 4-methyl-2-phenyl-4,5-dihydrooxazole
(3, 0.02 M) at -78 °C. The curve depicts the result of an unweighted least-
squares fit to kobsd ) k[n-BuLi]n (k ) (1.93 ( 0.01) × 10-3, n ) 0.94 (
0.03).
d[ArH]/dt ) k′[ArH]1[TMEDA]0[(n-BuLi)2(TMEDA)2]1 (4)
those of their deuterated analogues,25 confirm a rate-limiting
proton abstraction. Zeroing the IR baseline and monitoring the
reaction of a second aliquot of substrate affords no significant
change in the rate constant, showing that autocatalysis, auto-
inhibition, and other conversion-dependent effects are unim-
portant under these conditions.26 The results of the rate studies
are summarized in Table 1. Representative rate data are depicted
in Figures 1-3; additional data are included in Supporting
Information.
(n-BuLi)2(TMEDA)
(9)
2 + ArH f
[(n-BuLi)2(TMEDA)2(ArH)]q (5)
Relative Rate Constants. The ortholithiation rates of aryl
oxazolines are structure dependent as shown by the numbers in
(24) Arene-n-BuLi complexes were detected in the absence of coordinating
TMEDA. For leading references to analogous frequency shifts resulting
from oxazoline-metal complexation, see: (a) Braunstein, P.; Fryzuk,
M. D.; Le Dall, M.; Naud, F.; Rettig, S. J.; Speiser, F. Dalton Trans. 2000,
1067. (b) Bonnardel, P. A.; Parish, R. V.; Pritchard, R. G. Dalton Trans.
1996, 3185.
(25) (a) Arenes 3-d5, 4-d5, and 8-d5 were prepared from benzoyl-d5 chloride
and the corresponding amino alcohol following reported procedures (see
also ref 2c): Meyers, A. I.; Temple, D. L.; Haidukewych, D.; Mihelich,
E. D. J. Org. Chem. 1974, 39, 2787. (b) Arene 5-d1: Meyers, A. I.; Avila,
W. B. Tetrahedron Lett. 1980, 21, 3335. (c) See also ref 3.
(26) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624. (b) Caubere,
P. In ReViews of Heteroatom Chemistry; MYU: Tokyo, 1991; Vol. 4, pp
78-139.
The [(n-BuLi)2(TMEDA)2(ArH)]q stoichiometry is analogous
to that observed in benzene and anisole metalations8 and
(27) (a) Depue, J. S.; Collum, D. B. J. Am. Chem. Soc. 1988, 110, 5524. (b)
Reichardt, C. SolVents and SolVent Effects in Organic Chemistry; VCH:
New York, 1988; Chapter 5. (c) Lucht, B. L.; Collum, D. B. J. Am. Chem.
Soc. 1996, 118, 2217.
(28) We define the idealized rate law as that obtained by rounding the observed
reaction orders to the nearest rational order.
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A R T I C L E S
Chadwick et al.
consistent with generic triple ion-based transition structures 10
and 11, which are discussed in the context of the computational
studies. More conventional open dimers (12) are also evaluated
computationally.
Ortholithiations of arenes 4 and 8 appear to be mechanistically
complex. In both cases, plots of kobsd versus n-BuLi concentra-
tion furnish n-BuLi orders between 0.5 and 1.0 (Figure 3),
which, in conjunction with zeroth-order dependencies on the
TMEDA concentration, implicate the idealized rate law de-
scribed by eq 6 and the affiliated dimer- and monomer-based
mechanisms depicted in eqs 7 and 8, respectively.
existence of a single imaginary frequency. The relative Gibbs
free energies of activation (∆Gq, kcal/mol) at 298.15 K and 1.0
atm are shown under the structures. Selected geometric char-
acteristics of the calculated transition structures are archived in
Supporting Information. Isomeric structures displaying N- or
O-coordinated lithiums were calculated. The methoxy-substi-
tuted derivatives afforded transition structures and activation
energies for both syn and anti forms 18 and 19, respectively.
d[ArH]/dt ) k′[ArH]1[TMEDA]0[(n-BuLi)2(TMEDA)2]1 +
k′′[ArH]1[TMEDA]0[(n-BuLi)2(TMEDA)2]1/2 (6)
(n-BuLi)2(TMEDA)
(9)
2 + ArH f
[(n-BuLi)2(TMEDA)2(ArH)]q (7)
2 + ArH f
Caveats. In the following discussion, references to “stabili-
ties” or “stabilization” risk sounding linguistically and scientifi-
cally imprecise, but they simply refer to the relative free energies
of metalation described for monomers (eq 9, ∆Gmq), dimers (eq
1/2(n-BuLi)2(TMEDA)
(9)
[(n-BuLi)(TMEDA)(ArH)]q (8)
q
q
10, ∆Gd ), and triple ions (eq 15, ∆Gti ). Also, eq 15 represents
a fundamentally different transformation than those described
by eqs 9 and 10. In principle, the free energies reported in eq
15 can be adjusted by including the free energy of ionization
(eq 13) to allow for a direct comparison. In practice, the
calculated ionization energy in eq 13 is of no quantitative value
because of huge distortions imparted by DFT on ionizations.33
Although we discuss the structural details that influence the
monomer-, dimer-, and triple ion-based metalations, triple ions
and the other two classes are not compared directly.
We discuss triple ion-based transition structures 10 and 11 and
monomer-based transition structures 13 and 1429 below in the
context of computational studies.
Monomer-Based Ortholithiations. The rate studies provide
evidence that monomer-based metalations become competitive
for substrates that display relatively low reactivity (although
low reactivity may not be the key variable). The calculations
are only partially successful at mirroring experiment. The
relative free energies of monomer-based metalations described
generically by eq 9 are included under each transition structure.
The transition structure for the monomer-based ortholithiation
of benzene (20) serves as a benchmark. The planes crudely
defined by the TMEDA-lithium chelate, the aryl ring, and the
C2HLi fragment in 20 are nearly orthogonal. H-Li agostic
interactions are conspicuous.34
B. Density Functional Theory Calculations. Rate studies
implicate contributions from monomer- and dimer-based transi-
tion structures [(n-BuLi)(TMEDA)(ArH)]q and [(n-BuLi)2-
(TMEDA)2(ArH)]q, respectively. We investigated the reaction
coordinate computationally to examine specific issues, including
(1) N- versus O-directed lithiation, (2) the possible role of triple
ions, [(n-Bu)2Li-(ArH)//+Li(TMEDA)2]q,8 and (3) the origins
of substrate-dependent rates and mechanisms.
General. DFT calculations were performed with the Gaussian
03 package at the B3LYP/6-31G(d) level.30 MeLi was used as
a model for n-BuLi. Fully optimized structures were obtained
for arenes 2-4 and 8. Arene 5 was modeled using oxazoline
15. Although the ortholithiation of arene 16 was not investigated
experimentally, we examined it computationally for comparison.
Naked triple ion fragment, 17, was optimized and confirmed31
to be linear.32 We sampled initial geometries for reactants and
transition structures, and we established saddle points by the
q
∆Gm
1/2(MeLi)2(TMEDA)2 + ArH
8
[(MeLi)(TMEDA)(ArH)]q (9)
The monomer-based metalations display a high preference
for N- versus O-directed metalation35 and a high sensitivity to
steric effects. Thus, the transition structure for N-directed
ortholithiation of unsubstituted aryl oxazoline 2 displays
(29) For a discussion on triple ion versus monomer reactivity, see: Reich,
H. J.; Sikorski, W. H.; Gudmundsson, B. O¨ .; Dykstra, R. R. J. Am. Chem.
Soc. 1998, 120, 4035.
(30) Frisch, M. J.; et al. Gaussian 03, revision B.04; Gaussian, Inc.: Wallingford,
CT, 2004.
(31) A relaxed potential energy surface scan along the C-Li-C angle at the
B3LYP/6-31G(d) level of theory shows an exponential increase in energy
as the angle slightly deviates from linearity (see Supporting Information).
(32) (a) Hill, M. S.; Hitchcock, P. B. Organometallics 2002, 21, 220. (b)
Bildmann, U. J.; Mu¨ller, G. Organometallics 2001, 20, 1689. (c) Bock,
H.; Beck, R.; Havlas, Z.; Scho¨del, H. Inorg. Chem. 1998, 37, 5046. (d)
Romesberg, F. E.; Collum, D. B. J. Am. Chem. Soc. 1994, 116, 9187.
(33) Ramirez, A.; Lobkovsky, E.; Collum, D. B. J. Am. Chem. Soc. 2003, 125,
15376.
(34) Scherer, W.; McGrady, G. S. Angew. Chem., Int. Ed. 2004, 43, 1782 and
references cited therein.
(35) For other examples of lithium azaphilicity, see: (a) Lucht, B. L.; Collum,
D. B. J. Am. Chem. Soc. 1996, 118, 2217. (b) Remenar, J. F.; Collum,
D. B. J. Am. Chem. Soc. 1997, 119, 5573. (c) Remenar, J. F.; Collum,
D. B. J. Am. Chem. Soc. 1998, 120, 4081. (d) Ramirez, A.; Collum, D. B.
J. Am. Chem. Soc. 1999, 121, 11114.
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Ortholithiations of Aryl Oxazolines
A R T I C L E S
significant stabilization relative to the ortholithiation of benzene
(cf., 20 and 21). By contrast, the O-directed ortholithiation of
2 shows a surprisingly limited stabilization (cf., 20 and 22).
This pronounced N-selectivity is eliminated by methyl substit-
uents proximate to the nitrogen; transition structures 23 and 24
corresponding to O-directed lithiations can be found, whereas
the corresponding N-bound transition structures cannot. We
presume this difference results from steric interactions of the
oxazoline substituents with the chelated TMEDA ligand. The
difference also presents a significant conflict with experiment
as discussed below, however. The oxazines also display a
pronounced N versus O selectivity (cf., 25 and 26), but are
inferior to oxazolines at directing lithiation.
ancillary methoxy substituent does not facilitate monomer-based
metalations.
Although we have no experimental data on the cooperative
effects of oxazolines and fluoro substituents because the
metalations are too fast, we thought it would be instructive to
probe the role of meta fluoro substituents computationally.
Comparing 21 with 31 as well as 22 with 32 suggests that the
monomer-based metalations are relatively insensitive to induc-
tive effects. In fact, the fluoro-directed metalations without
coordination by the oxazolinyl group appear to be equally facile
(cf., 33 and 31).
It is unclear (to us, at least) how the well-documented
cooperative directing effects of meta substituents2 could derive
from concurrent interactions of both moieties with lithium in
all but exceptional cases; the geometries appear to be unreason-
able. By inference, the cooperativity arises from induction by
an ancillary (non-coordinated) substituent. The roles of meta
substituents on the ortholithiations of aryl oxazolines were
probed as follows.
Monomer-based ortholithiations are very sensitive to the
orientation of ancillary methoxy moieties. Syn-oriented methoxy
substituents appear to destabilize the monomer-based transitions
structures; none could be located, presumably because of severe
steric effects. (This relationship is not the same for triple ions;
see later). Conversely, anti-oriented methoxy groups allow for
either oxazoline- or methoxy-directed metalations (27-30). The
most stable form (27) displays an N-Li interaction. Interest-
ingly, the methoxy moiety of 27 adds little stability when
compared with unsubstituted analogue 21, suggesting that an
Having examined the inductive effects of fluoro and methoxy
moieties on oxazoline-directed ortholithiations, we posed the
question in reverse: Does the oxazoline function inductively
as an ancillary activating group for methoxy- and fluoro-directed
ortholithiations by monomers? Comparison of transition struc-
ture 29 with the most favorable anisole-derived analogue, 35,
indicates that the addition of a non-coordinating oxazoline meta
9
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A R T I C L E S
Chadwick et al.
to the methoxy group does not grant any stabilization. Similarly,
an ancillary oxazoline does not facilitate a fluoro-directed
ortholithiation (cf., 34 and 36).
Open Dimer- and Broken Dimer-Based Ortholithiations.
There is mounting evidence that dimer-based organolithium
chemistry may involve partial dimer scission or so-called open
dimers.11,36 Nonetheless, it is unclear how congestion in a
transition structure of stoichiometry [(n-BuLi)2(TMEDA)2 (ArH)]q
present an interesting question: Could complexation of a
monomer (or, more generally, a Lewis acid) at the remote
heteroatom of an oxazoline facilitate metalation directed by the
second heteroatom? The calculations suggest the answer is no.
By comparing the metalation of the simple oxazoline (eq 11)
with that of a monomer-complexed oxazoline (eq 12), we found
the ancillary monomer fragment to be highly deactivating even
in the best-case scenario in which the cost of complexing the
monomer fragment is discounted. The deactivation by a pre-
complexed monomer could be due, in part, to the reduced Lewis
basicity of the directing heteroatom, which is key in monomer-
based metalations. Most important, simple dimer-based meta-
lations appear to be uncompetitive with monomer-based cases.
For these reasons, we turned to triple ions.
Triple Ion-Based Ortholithiations. Triple ion-based meta-
lations (see 44 and 45) are described by eqs 13-15. Unfortu-
nately, DFT calculations grossly exaggerate energies affiliated
with such ionizations and are not particularly well suited for
ascertaining the ion pairing energies.33,37 However, because the
pairing energies of Me2Li- (17) and [(Me2Li)(ArH)-]q fragments
with +Li(TMEDA)2 (eq 14) should largely cancel37b the relatiVe
arene-dependent activation energies can be evaluated by omitting
the +Li(TMEDA)2 altogether (eq 15).
could be tolerated in the open dimer motif (which was our
motivation for turning to triple ions in previous studies).8a Still,
we considered a number of transition structures, 37-39,
summarized in Chart 2. The free energies are described by
eq 10.
q
∆Gd
(MeLi)2(TMEDA)2 + ArH
8
(MeLi)2(TMEDA)2 ∆G°8 (Me2Li)- + +Li(TMEDA)2 (13)
[(MeLi)2(TMEDA)2(ArH)]q (10)
(Me2Li)- + +Li(TMEDA)2 + ArH f
[(Me2Li)(ArH)-]q + +Li(TMEDA)2 (14)
Transition structure 37 preserves the connectivities of the
(MeLi)2(TMEDA)2 cyclic dimer, whereas structures 38 and 39
represent isomeric open dimers. Attempting to find transition
structures corresponding to 37-39, however, invariably led to
highly distorted structures 40 and 41, which manifested an
extraordinarily long (>2.3 Å) Me-Li bond. Indeed, fully
fragmented dimers-broken dimers-described as 42 and 43
were found to be 4-5 kcal/mol more stable than 40 and 41.
q
∆Gti
(Me2Li)- + ArH
8 [(Me2Li)(ArH)-]q
(15)
The triple ion-based transition structures derived from aryl
oxazolines are compared with the analogous transition structure
for the ortholithiation of benzene (46) as a benchmark. We
reiterate that the free energies for monomer-based metalations
q
(eq 9, ∆Gmq) and triple-ion-based metalations (eq 15, ∆Gti )
cannot be compared.38
All triple ion-based transition structures display H-Li agostic
interactions.34 The existence of an X-Li interaction (XdN or
O) correlates with the orientation of the plane defined by the
CH3-Li-CH3 triple ion fragment involved in the deprotonation
relative to the plane defined by the arene ring: Transition
structure 46 for the lithiation of benzene shows planes that are
The free energies of activation of stretched and broken dimers
40-43 are >40 kcal/mol, which, by comparison with monomer-
based metalations, are enormous. These results did, however,
(36) For discussions of open dimer-based mechanisms for reactions of alkyl-
lithiums, see: (a) Kaufmann, E.; Schleyer, P. v. R.; Houk, K. N.; Wu,
Y.-D. J. Am. Chem. Soc. 1985, 107, 5560. (b) Nakamura, E.; Nakamura,
M.; Koga, N.; Morokuma, K. J. Am. Chem. Soc. 1993, 115, 11016. (c)
Pratt, L. M.; et al. J. Org. Chem. 2003, 68, 6387 and references cited therein.
(d) For additional leading references to spectroscopic, crystallographic, and
kinetic evidence of open dimers, see: Zhao, P.; Collum, D. B. J. Am. Chem.
Soc. 2003, 125, 14411.
(38) Other computational studies considering monomer-based ortholithiations:
(a) Balle, T.; Begtrup, M.; Jaroszewski, J. W.; Liljefors, T.; Norrby, P.-O.
Org. Biomol. Chem. 2006, 7, 1261. (b) Nguyen, T.-H.; Chau, N.-T.-T.;
Castanet, A.-S.; Nguyen, K.-P.-P.; Mortier, J. Org. Lett. 2005, 7, 2445. (c)
van Eikema Hommes, N. J. R.; Schleyer, P. v. R. Tetrahedron 1994, 50,
5903. (d) van Eikema Hommes, N. J. R.; Schleyer, P. v. R. Angew. Chem.,
Int. Ed. Engl. 1992, 31, 755 and references cited therein. (e) See ref 11b.
(37) (a) B3LYP/6-31G(d) computations give a free energy of ionization (eq
13) of ∆G° ) 28.9 kcal/mol. (b) Cioslowski, J.; Piskorz, P.; Schirneczek,
M.; Boche, G. J. Am. Chem. Soc. 1998, 120, 2612.
9
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Ortholithiations of Aryl Oxazolines
A R T I C L E S
Chart 2. Possible Dimer-Based Mechanisms
oxazoline methyl substituent and the ancillary (nonmetalating)
methyl group are important.31,32,39 The absence of such an
interaction in 50 makes N- and O-directed ortholithiations
comparable. A second methyl group has an attenuated effect
(cf., 51 and 52). By contrast, relative rate constants in Chart 1
reveal little effect of the first methyl group but a 20-fold
deceleration by the second (cf., 2, 3 and 4; Chart 1). We hasten
to add that substituent effects on O- versus N-directed lithiations
are likely to be underestimated by the MeLi model system.
The ortholithiation of oxazine 8 affords activation energies
that are higher than those calculated for oxazoline 2 (cf., 47
and 53 as well as 48 and 54), consistent with experiment
(Chart 1). The rotation of the CH3-Li-CH3 plane in 53 suggests
nearly orthogonal, whereas the two planes in transition structures
47, 48, and all subsequent cases studied are nearly coincident.
q
The oxazoline group reduces ∆Gti by 5 kcal/mol when com-
q
pared with the analogous ∆Gti derived from benzene (cf., 46
and 47). The N-Li interaction is preferred to the O-Li contact
by 1.3 kcal/mol (cf., 47 and 48). This difference is smaller than
we expected given the results from monomer-based metalations.
that the destabilization in 53 may derive from steric interactions
between the methylene group R to the heteroatom and the triple
ion. The Lewis basicity of the nitrogen and oxygen also might
be sensitive to ring size.40
Isomeric transition structures 55-60 were located for the
triple ion-based ortholithiation of methoxy-substituted oxazoline
15. The results support previous assertions8a that only syn-
oriented methoxy groups (see 18) are stabilizing in the triple
ion-based transition structures. The small stabilization of 57 and
58 relative to 47 and 48 (respectively) is in accord with experi-
A methyl group on the carbon R to the oxazoline nitrogen in
arene 3 retards the N-directed ortholithiations when compared
with the N-directed ortholithiations of unsubstituted aryl oxa-
zoline 2 (cf., 49 and 47). A distinct twisting of the plane defined
by the CH3-Li-CH3 fragment and reduction of the CH3-Li-
CH3 angle in 49 suggests that steric interactions between the
(39) (a) Tahara, N.; Fukuda, T.; Iwao, M. Tetrahedron Lett. 2002, 43, 9069.
(b) Wehman, E.; van Koten, G.; Erkamp, C. J. M.; Knotter, D. M.;
Jastrzebski, J. T. B. H.; Stam, C. H. Organometallics 1989, 8, 94.
(40) (a) Rozeboom, M. D.; Houk, K. N.; Searles, S.; Seyedrezail, S. E. J. Am.
Chem. Soc. 1982, 104, 3448. (b) Arnett, E. M.; Wu, C. Y. J. Am. Chem.
Soc. 1962, 84, 1684. (c) Cook, A. G.; Absi, M. L.; Bowden, V. K. J. Org.
Chem. 1995, 60, 3169 and references cited therein.
9
J. AM. CHEM. SOC. VOL. 129, NO. 8, 2007 2265

A R T I C L E S
Chadwick et al.
ment (Chart 1). Importantly, the oxygen atom of a syn-oriented
methoxy group cannot interact with lithium. Some activation
by syn-oriented methoxy groups occurs despite potentially de-
stabilizing steric interactions, and it likely stems from induc-
tion.41 Transition structures 55 and 56, with anti-oriented meth-
oxy groups, are significantly destabilized compared to their un-
substituted counterparts. We previously posited that electron re-
pulsion between the lone pairs of the oxygen of the anti-oriented
methoxy group and the electron rich triple ion may be destab-
ilizing.8a The markedly different influences of methoxy moieties
on monomer- and triple ion-based metalations are discussed
later.
crepancy between theory and experiment. We wonder whether
a fundamentally different mechanism is intervening (vide infra).
Discussion
We examined cooperative effects in meta fluoro-substituted
aryloxazolines and located four transition structures. Transition
structures 61 and 62 display oxazoline-Li coordination, whereas
63 and 64 display F-Li interactions. Although F-Li interactions
are stabilizing relative to their MeO-Li counterparts by >4
kcal/mol (cf., 59 and 63 as well as 60 and 64),42 coordination
to the oxazoline group is still preferred. Interestingly, introduc-
Oxazolines are one of the prominent directing groups in the
vast literature of ortholithiation.43 Substituents on the oxazoline
often influence the rate of metalation, preclude side reactions,
and control selectivities.17,44 n-BuLi/TMEDA-mediated ortholithi-
ations of aryl oxazolines described herein show that the
substituent-dependent rates are affiliated with changes in
mechanism. There are, however, many factors contributing to
the rates and mechanisms.
q
tion of a non-coordinating fluoro substituent reduces ∆Gti by
>4 kcal/mol (cf., 47 and 61).
Summary of Rate Studies. Relative rate constants in Chart
1 confirm that substituents on strongly ortho-directing oxazoline
and arene rings markedly influence the rates. Detailed rate
studies of 3, 4, 5, and 8 reveal substrate-dependent mechanisms
(Table 1). By example, aryl oxazolines 3 and 5, bearing sterically
demanding substituents, ortholithiate via exclusively dimer-
based mechanisms described generically by eqs 4 and 5. Dimer-
based metalations were the only detectable mechanisms ob-
served from analogous lithiations of benzene, anisole, and related
alkoxy-substituted arenes.8 Conversely, ortholithiation of arenes
4 and 8, the most unreactive substrates, appear to proceed by
both dimer- and monomer-based mechanisms (eqs 7 and 8).
Mechanisms. The rate data define the stoichiometries of the
rate-limiting transition structures and, with the aid of kinetic
isotope effects, confirm that the rate-limiting steps involve
proton transfers. There are, however, many subtle issues
presented by the ortholithiations of oxazolines that cannot be
addressed experimentally. Computational studies allowed us to
probe underlying steric and electronic influences of substituents.
The detailed comparisons delineated in the Results section are
not repeated. Readers also may note the absence of direct
numerical comparisons of monomer-, dimer-, and triple ion-
based ortholithiations for reasons explicitly noted above. We
do, however, find that the influences of the ortholithiation
mechanisms in isolation offer considerable insights into how
the structure of the substrate influences the rates and mechanisms
of ortholithiation.
One can gain insight into the inductive influence of the
oxazoline ring on ortholithiation by comparing methoxy- and
fluorine-directed ortholithiations bearing uncoordinated oxazo-
lines with metalations of anisole and fluorobenzene (cf., 60 and
65 as well as 64 and 66). The non-coordinating oxazoline affords
<0.4 kcal/mol of stabilization, suggesting that induction is
minimal. By inference, the ∼3.0 kcal/mol of stabilization by a
coordinated oxazoline group (cf., 57 and 65 as well as 61 and
66) largely derives from the N-Li interaction. The relative rate
constants for 4 and 7 (Chart 1) show that a second oxazoline
moiety is highly activating. The failure of the calculations to
mimic a large inductive effect by the oxazoline suggests a dis-
Monomer-based metalations exemplified by generic transition
structures 13 and 14 are viable and relatively straightforward.
By contrast, dimer-based metalations pose a conundrum in that
(43) (a) Govindasamy, M.; Singh, H. B. Acc. Chem. Res. 2002, 35, 226. (b)
Overman, L. E.; Owen, C. E.; Zipp, G. G. Angew. Chem., Int. Ed. 2002,
41, 3884. (c) Iwamoto, K.; Chatani, N.; Murai, S. J. Org. Chem. 2000, 65,
7944. (d) Arnoldi, A.; Bassoli, A.; Borgonovo, G.; Merlini, L.; Morini, G.
J. Agric. Food Chem. 1997, 45, 2047. (e) Evans, P. A.; Nelson, J. D.;
Stanley, A. L. J. Org. Chem. 1995, 60, 2298. (f) Misra, R. N.; Brown,
B. R.; Sher, P. M.; Patel, M. M.; Hall, S. E.; Han, W.-C.; Barrish, J. C.;
Kocy, O.; Harris, D. N.; Goldenberg, H. J.; Michel, I. M.; Schumacher,
W. A.; Webb, M. L.; Monshizadegan, H.; Ogletree, M. L. J. Med. Chem.
1993, 36, 1401. (g) Sibi, M. P.; Miah, M. A. J.; Snieckus, V. J. Org. Chem.
1984, 49, 737. (h) Ellefson, C. R. J. Org. Chem. 1979, 44, 1533.
(44) (a) Geisler, F. M.; Helmchen, G. J. Org. Chem. 2006, 71, 2486. (b) Reuman,
M.; Meyers, A. I. Tetrahedron 1985, 41, 837.
(41) For a discussion on anti-MeO-Li interactions, see: Bauer, W.; Schleyer,
P. v. R. J. Am. Chem. Soc. 1989, 111, 7191.
(42) F-Li interactions are stabilizing: (a) Leharie, M.-L.; Scopelliti, R.; Severin,
K. Inorg. Chem. 2002, 41, 5466. (b) Wiberg, K. B.; Sklenak, S.; Bailey,
W. F. J. Org. Chem. 2000, 65, 2014. (c) Kremer, T.; Junge, M.; Schleyer,
P. v. R. Organometallics 1996, 15, 3345. (d) Streitwieser, A.; Abu-
Hasanyan, F.; Neuhaus, A.; Brown, F. J. Org. Chem. 1996, 61, 3151. (e)
Stalke, D.; Klingebiel, U.; Sheldrick, G. M. Chem. Ber. 1988, 121, 1457.
9
2266 J. AM. CHEM. SOC. VOL. 129, NO. 8, 2007

Ortholithiations of Aryl Oxazolines
A R T I C L E S
juxtaposition of two n-BuLi fragments, two TMEDA ligands,
and the substrate is not easy to imagine within the dimer motif.
Dimer-like mechanisms examined are summarized in Chart 2.
We considered cyclic and open dimer-based transition structures
(37-39), and found that they invariably stretched the C-Li
bond (40 and 41) akin to related transition structures calculated
by Saa´.11b We subsequently discovered more stable “broken
dimers”-transition structures in which complete scission of the
dimer is tantamount to reaction requiring two monomers (42
and 43). Although the stretched and broken dimers are provoca-
tive, computational evidence suggests that the ancillary mono-
mer appended on the oxazoline ring is highly counterproductive.
Accordingly, we turned to triple ion-based transition structures
(44 and 45). Triple ions have been studied spectroscopically,
crystallographically, and computationally but have been slow
to gain the attention of nonspecialists.12 The remaining issues
are discussed in the context of these general classes of
mechanism.
N- versus O-Directed Ortholithiation. Sammakia and
Latham used a constrained substrate (eq 3) to show that sec-
BuLi/THF-mediated metalations of aryl oxazolines proceed via
N- rather than an O-directed mechanism.17 Their conclusion
seems reasonable in light of the δ+O-CdNδ- polarization of
the imino moiety.45 Computational studies suggest that the bal-
ance between N- and O-directed lithiation may be more subtle.
Triple ion-based metalation of the parent oxazoline 2 favors
N-Li versus O-Li interactions, but the difference is small. By
contrast, the preference for N-directed ortholithiation is much
more dramatic in the monomer-based metalations. Interestingly,
monomeric lithium amides also display an inordinate azaphilicity
compared to their dimeric counterparts.35 Overall, the azaphi-
licities versus the oxaphilicities of the two ortholithiation
mechanisms are quite different. The devil is in the details,
however, in that the inherent nitrogen versus oxygen selectivity
is superseded by substituents on the oxazolinyl ring.
based metalations are predicted to be substantially more sensitive
than the triple ion-based cases to the steric demands of the
oxazoline substituents. This observation represents the first of
two significant disagreements of theory and experiment. Ac-
cording to theory, attenuated rates should correlate with a
disproportionate suppression of the sterically sensitive monomer-
based metalation. Conversely, monomer-based metalations were
detected experimentally for oxazolines 4 and 8. Although it
might be tempting to invoke O-directed transition structures 69
or 70, calculations also suggest that such monomer-based,
O-directed lithiations are problematic. Of course, MeLi may
be a poor model for n-BuLi, but that seems dismissive.
Cooperative Directing Effects. We find cooperative directing
effects by meta-disposed directing groups to be vexing. The
cooperativity is not in doubt, as evidenced by high regioselec-
tivities46,47 and high metalation rates;2,44,48 how two groups
cooperate is less clear. Some have suggested, for example, that
two meta-disposed groups coordinate lithium concurrently in
the transition structure.49 We find such models unconvincing
and lacking support (although we revisit this model for one case
below). Two groups that acidify the ortho protons inductively
certainly could function cooperatively, and the influences may
even be quantitatively additive. Schlosser has contributed
significantly to understanding such inductive effects.7 The most
interesting form of cooperation, however, may arise when one
group displays a penchant for interaction with lithium whereas
the second groupswhat we call the ancillary or uncoordinated
groupsacidifies the ortho proton inductively. The two directing
substituents play fundamentally different roles. Oxazolines
appear to strongly coordinate lithium, and computations suggest
oxazolinyl moieties have no tendency to activate inductively
(vide infra). Thus, cooperativity in aryl oxazoline metalations
requires an inductive ancillary group at the meta position. Of
course, substituents on the oxazoline ring (Me versus H), the
choice of directing group (O versus N), and the mechanistic
pathway (monomer versus triple ion) all influence cooperativity.
(45) Durig, J. R.; Riethmiller, S.; Li, Y. S. J. Chem. Phys. 1974, 60, 253.
(46) Examples of regioselective lithiation at position 2 in 1,3-orthodirecting
disubtituted arenes include the following. (i) Low selectivity: (a) Freskos,
J. N.; Morrow, G. W.; Swenton, J. S. J. Org. Chem. 1985, 50, 805. (ii)
High selectivity: (b) Harder, S.; Meijboom, R.; Moss, J. R. J. Organomet.
Chem. 2004, 689, 1095. (c) Saednya, A.; Hart, H. Synthesis 1996, 1455.
(d) Kostas, I. D.; Gruter, G.-J. M.; Akkerman, O. S.; Bickelhaupt, F.;
Kooijman, H.; Smeets, W. J. J.; Spek, A. L. Organometallics 1996, 15,
4450. (e) Pfeffer, M.; Urriolabeitia, E. P.; de Cian, A.; Fischer, J. J.
Organomet. Chem. 1995, 494, 187. (f) Cho, I. S.; Gong, L.; Muchowski,
J. M. J. Org. Chem. 1991, 56, 7288. (g) Harder, S.; Boersma, J.; Brandsma,
L.; Kanters, J. A.; Bauer, W.; Schleyer, P. v. R. Organometallics 1989, 8,
1696. (h) Kress, T. H.; Leanna, M. R. Synthesis 1988, 803. (i) Guillaumet,
G.; Hretani, M.; Coudert, G. Tetrahedron Lett. 1988, 29, 475. (j) Becker,
A. M.; Irvine, R. W.; McCormick, A. S.; Russell, R. A.; Warrener, R. N.
Tetrahedron Lett. 1986, 27, 3431. (k) Terheijden, J.; van Koten, G.; van
Beek, J. A. M.; Vriesema, B. K.; Kellogg, R. M.; Zoutberg, M. C.; Stam,
C. H. Organometallics 1987, 6, 89. (l) Freskos, J. N.; Morrow, G. W.;
Swenton, J. S. J. Org. Chem. 1985, 50, 805. (m) Meyers, A. I.; Pansegrau,
P. D. Tetrahedron Lett. 1984, 25, 2941. (n) Edgar, K. J.; Bradsher, C. K.
J. Org. Chem. 1982, 47, 1585. (o) Yamamoto, H.; Maruoka, K. J. Org.
Chem. 1980, 45, 2739. (p) De Silva, S. O.; Reed, J. N.; Snieckus, V.
Tetrahedron Lett. 1978, 51, 5099. (q) Ziegler, F. E.; Fowler, K. W. J. Org.
Chem. 1976, 41, 1564.
(47) For example, if the ortho selectivity of the metalation of resorcinol dimethyl
ether arises exclusively from a formal delivery-based mechanism via a single
MeO-Li interaction, the lithiation should afford a statistical 1:1 mixture
of 2,6-dimethoxy- and 2,4-dimethoxyphenyllithiums.
(48) (a) Paquette, L. A.; Schulze, M. M. Tetrahedron Lett. 1993, 34, 3235. (b)
Thornton, T. J.; Jarman, M. Synthesis 1990, 295. (c) Beak, P.; Brown,
R. A. J. Org. Chem. 1982, 47, 34.
(49) (a) Winkle, M. R.; Ronald, R. C. J. Org. Chem. 1982, 47, 2101. (b)
Townsend, C. A.; Bloom, L. M. Tetrahedron Lett. 1981, 22, 3923. (c)
Christensen, H. Synth. Commun. 1975, 5, 65. (d) Ellison, R. A.; Griffin,
R.; Kotsonis, F. N. J. Organomet. Chem. 1972, 36, 209. (e) See also
ref 11.
Effects of Oxazoline Substituents. The computational studies
show that substituents on the oxazoline ring retard the ortholithi-
ations in several ways. These substituents clash with the ancillary
(nonreacting) alkyllithium fragment in triple ion 67 and with
the TMEDA ligand on monomer-based transition structure 68.
The transition structures all show distortions consistent with
steric relief and manifest moderately elevated activation energies
compared with those of the non-methylated cases. The monomer-
9
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A R T I C L E S
Chadwick et al.
Summary and Conclusions
We briefly consider ancillary methoxy, fluoro, and oxazolinyl
substituents as follows.
The rate and computational studies of the ortholithiation of
aryloxazolines described herein underscore a seemingly straight-
forward question: How are ortholithiations directed? The rate
studies demanded that we focus on monomer- and dimer-based
mechanisms. The issue is not binary, however. A number of
dimer-based mechanisms were considered, of which triple ions
captivated the bulk of our attention. Both monomer- and triple
ion-based mechanisms displayed sensitivities to substituents on
the oxazoline and arene rings. The issue of N- versus O-directed
lithiation could not be put to rest as readily as we anticipated;
both appeared to be competitive depending on the choice of
substrate and mechanism.
In previous studies we concluded that methoxy moieties of
anisoles do not necessarily coordinate to lithium during ortholithi-
ation even when it is geometrically possible. The results
described herein are in agreement in that we find no evidence
that lithiations are directed by MeO-Li interactions. An
interesting question resurfaced: Does an uncoordinated methoxy
orient syn or anti (cf., 21 and 22) to the proton being abstracted?
Computations suggest that only a syn orientation is stabilizing
despite potentially problematic steric effects. We suspect the
lone pairs on the anti form are destabilizing but have no direct
support. There appears to be a pronounced mechanism depen-
dence on the orientation of the methoxy moiety. Triple ion-
based transition structures benefit from syn-oriented methoxy
groups, whereas monomer-based analogues do not. Indeed,
oxazoline 5 shows a modest acceleration in comparison with 4
(Chart 1), and the rate studies show no evidence of a monomer-
based pathway intervening.
Although fluoro-substituted oxazolines are too reactive to
study, the pronounced activation by fluorine is still fascinating.
Computational studies suggest that fluorine is a versatile
directing group, facilitating ortholithiations via either a distinct
F-Li interaction or simple induction. The two roles show a
distinct dependence on mechanism. The capacity of fluorine to
direct ortholithiations through an F-Li interaction is calculated
to be particularly important in the sterically sensitive monomer-
based metalations, presumably because of the low steric
demands of a F-Li interaction. The capacity of fluorine to
inductively facilitate the metalation as an ancillary group is more
pronounced in triple ion-based pathways, which appear to be
pKa sensitive.
We finish this discussion by considering cooperative effects
imparted by an ancillary oxazoline ligand and confront the
second significant disagreement between theory and experiment.
The experimental data are unequivocal: bisoxazoline 7 ortholithi-
ates g100 times faster than its monooxazoline counterpart 4.
Computations, however, reveal no evidence that an uncoordi-
nated oxazoline promotes ortholithiation. Although one could
blame the MeLi model or computational failure, it seems
possible that the high reactivity observed for 7 stems from a
fundamental change in mechanism. A bis-chelated, monomer-
based transition structure such as 71 is appealing on first
inspection, but computations show that the distances are
unreasonable given the small radius of lithium. Interestingly,
the MeLi analogue of ansa-bridged dimer 72 can be found
computationally, and displays a reasonable geometry, but
attempts to include coordinated TMEDA ligands cause reversion
to stretched dimers noted above.
Possibly, the question that most demands an answer pertains
to polyfunctional substrates: How do meta-disposed sub-
stituents direct ortholithiation cooperatively? This issue is
enormously important given the prevalence of ortholithiation
2,5,6,43
in the synthesis of complex arenes and heteroarenes.
Substrate-, base-, and solvent-dependent regioselectivities3
observed in ortholithiations likely derive from mechanism-
dependent cooperative effects. Directed arene lithiation is often
presented simplistically, but it is not simple. We conclude that
the two groups most often serve different rolessone as a formal
directing group via a distinct substrate-lithium interaction and
the other as a non-coordinating ancillary group activating the
metalation inductively.
In closing, we wish to underscore the synergies offered by
experimental and computational methods: The rate data focus
the calculations by defining the stoichiometries of the rate-
limiting transition structures, whereas the calculations offer
details that are unavailable from experiment. It is a tribute to
computational chemistry that the computational methods can
play the dominant role in shaping mechanistic hypotheses.
Experimental Section
Reagents and Solvents. Substrates were prepared using literature
procedures described in the Supporting Information. Pentane was
distilled from blue solutions containing sodium benzophenone ketyl
with approximately 1% tetraglyme to dissolve the ketyl. The diphe-
nylacetic acid used to determine n-BuLi solution titers was recrystallized
from methanol and sublimed at 120 °C under full vacuum.50 Air- and
moisture-sensitive materials were manipulated under argon using
standard glove box, vacuum line, and syringe techniques.
Kinetics. The rate studies were carried out as briefly described in
the text and in detail previously.8,51
Acknowledgment. We thank the National Science Foundation
for direct support of this work as well as DuPont Pharmaceu-
ticals, Merck Research Laboratories, Pfizer, Sanofi-Aventis,
R. W. Johnson, Boehringer-Ingelheim, and Schering-Plough for
indirect support.
Supporting Information Available: Experimental procedures,
rate data, tabular and graphical presentation of computational
results, and complete refs 30 and 36c. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA068057U
(50) Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41, 1879.
(51) Sun, X.; Collum, D. B. J. Am. Chem. Soc. 2000, 122, 2452.
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2268 J. AM. CHEM. SOC. VOL. 129, NO. 8, 2007